Search

Abstract: Among the seven serotypes (A–G), type A botulinum neurotoxin (BoNT/A) is the most prevalent etiologic agent and the most potent serotype to cause foodborne botulism, characterized by flaccid muscle paralysis. Upon ingestion, BoNT/A crosses epithelial cell barriers to reach lymphatic and circulatory systems and blocks acetylcholine release at the pre-synaptic cholinergic nerve terminals of neuromuscular junctions (NMJs) resulting in paralysis. One of the unique features of BoNT/A intoxication is its neuroparalytic longevity due to its persistent catalytic activity. The persistent presence of the toxin inside the cell can induce host cell responses. To understand the pathophysiology and host response at the cellular level, gene expression changes upon exposure of human HT-29 colon carcinoma (epithelial) and SH-SY5Y neuroblastoma cell lines to BoNT/A complex were investigated using microarray analysis. In HT-29 cells, 167 genes were up-regulated while 60 genes were down-regulated, whereas in SH-SY5Y cells about 223 genes were up-regulated and 18 genes were down-regulated. Modulation of genes and pathways involved in neuroinflammatory, ubiquitin–proteasome degradation, phosphatidylinositol, calcium signaling in SH-SY5Y cells, and genes relevant to focal adhesion, cell adhesion molecules, adherens and gap junction related pathways in HT-29 cells suggest a massive host response to BoNT/A. A clear differential response in epithelial and neuronal cells indicates that the genes affected may play a distinct role in BoNTs cellular mode of action, involving these two types of host cells. [Copyright &y& Elsevier]

Abstract: Condylomata acuminata (CA) caused by human papillomavirus (HPV) is a common sexually transmitted disease with half a million new cases diagnosed in the United States per year and the annual increase in incidence in China. Recurrence is a major challenge for CA treatment. Recently, we demonstrated that FOXP3+ regulatory T (Treg) cells mediate the immunosuppression in large genital warts. Here, we further report that low-dose cyclophosphamide (CY), a conventional chemotherapy drug, can effectively prevent the recurrence of large CA in clinical patients after laser therapy. Surprisingly, although 9 out of 52 patients recur six weeks after the combination treatment, the re-administration of low-dose CY alone completely eliminates most recurred lesions. We provide evidence that low-dose CY not only depletes patients'' Treg cells and enhances function of HPV-specific T cells and NK cells in the periphery, but also ameliorates the immune milieu of the lesion site, leading to the elimination of remnant viruses. These findings have important clinical significance, and potentially lead to a therapeutic breakthrough for the treatment of CA. [Copyright &y& Elsevier]

In view of the negative regulatory effect of leucine-rich repeat and immunoglobulin-like domain-containing nogo receptor-interacting protein 1 (LINGO-1) on neurons, an antibody against LINGO-1 (anti-LINGO-1 antibody) was herein administered to 10-month-old APP/PS1 transgenic Alzheimer's disease (AD) mice for 2 months as an experimental intervention. Behavioral, stereology, immunohistochemistry and immunofluorescence analyses revealed that the anti-LINGO-1 antibody significantly improved the cognitive abilities, promoted adult hippocampal neurogenesis (AHN), decreased the amyloid beta (Aβ) deposition, enlarged the hippocampal volume, and increased the numbers of total neurons and GABAergic interneurons, including GABAergic and CCK-GABAergic interneurons rich in cannabinoid type 1 receptor (CB1R), in the hippocampus of AD mice. In contrast, this intervention significantly reduced the number of GABAergic interneurons expressing LINGO-1 and CB1R in the hippocampus of AD mice. More importantly, we also found a negative correlation between LINGO-1 and CB1R on GABAergic interneurons in the hippocampus of AD mice, while the anti-LINGO-1 antibody reversed this relationship. These results indicated that LINGO-1 plays an important role in the process of hippocampal neuron loss in AD mice and that antagonizing LINGO-1 can effectively prevent hippocampal neuron loss and promote AHN. The improvement in cognitive abilities may be attributed to the improvement in AHN, and in the numbers of GABAergic interneurons and CCK-GABAergic interneurons rich in CB1Rs in the hippocampus of AD mice induced by the anti-LINGO-1 antibody. Collectively, the double target effect (LINGO-1 and CB1R) initiated by the anti-LINGO-1 antibody may provide an important basis for the study of drugs for the prevention and treatment of AD in the future. [Display omitted] • An anti-LINGO-1 antibody ameliorates cognitive impairment in AD mice. • An anti-LINGO-1 antibody ameliorates the amyloid beta burden in the hippocampus of AD mice. • An anti-LINGO-1 antibody promotes adult hippocampal neurogenesis in AD mice. • An anti-LINGO-1 antibody increases the abundance of CB1R-rich CCK-GABAergic interneurons in AD mice. [ABSTRACT FROM AUTHOR]

Abstract: Human astrovirus is one of the important causes for viral gastroenteritis in young children. In previous study where we examined the molecular epidemiology of human astrovirus (HAstV) infection in infants in Wuhan City, we isolated and identified a new subtype (WH1859) of HAstV genotype 3 from an infant with diarrhea. The sequence analysis of this strain showed that the complete region of ORF2 of WH1859 contains 2385-bp of nucleotides that encode 795 amino acids. Because WH1859 strain has the identity of less than 95% with the distance of more than 0.05 to the reference strains of HAstV-3, WH1859 represents a distinct subtype within HAstV-3 strains. Further studies are needed to determine the role of this new subtype strain of HAstV in viral gastroenteritis among young children. [Copyright &y& Elsevier]

Abstract: Hypoxia-inducible factor-1 (HIF-1) represents an important tumor-selective therapeutic target for solid tumors. In search of novel small molecule HIF-1 inhibitors, 5400 natural product-rich extracts from plants, marine organisms, and microbes were examined for HIF-1 inhibitory activities using a cell-based reporter assay. Bioassay-guided fractionation and isolation, followed by structure elucidation, yielded three potent natural product-derived HIF-1 inhibitors and two structurally related inactive compounds. In a T47D cell-based reporter assay, manassantin B1, manassantin A, and 4-O-methylsaucerneol inhibited hypoxia-induced HIF-1 activation with IC50 values of 3, 3, and 20nM, respectively. All three compounds are relatively hypoxia-specific inhibitors of HIF-1 activation, in comparison to other stimuli. The hypoxic induction of HIF-1 target genes CDKN1A, VEGF, and GLUT-1 were also inhibited. These compounds inhibit HIF-1 by blocking hypoxia-induced nuclear HIF-1α protein accumulation without affecting HIF-1α mRNA levels. In addition, preliminary structure–activity studies suggest specific structural requirements for this class of HIF-1 inhibitors. [Copyright &y& Elsevier]

Energy and water resources are drawing increasing attention in China as indispensable elements of economic development and social stability. Energy and water are interconnected in economic systems. Although the nexus between them has been widely studied, few insights can be acquired by the intermediate transmission pressures across supply chains. Combing betweenness-based method and multi-regional input-output (MRIO) analysis, we, in this study, identified critical transmission sectors and main driving factors resulting from the usage structure. In details, we found that Metallurgy (S14) in Shandong, Henan, Jiangxi, Anhui, Sichuan, Zhejiang, Hunan, and Jiangsu , Electricity and hot water production and supply (S22) in Beijing and Guizhou , and Nonmetal production (S13) in Henan are the most critical transmission sectors bearing energy-water nexus pressures, ranking at the top 100 in China's supply chain networks. Roughly, the usage structure was mainly dominated by fixed capital formation, urban household consumption and trade export, and therefore should be given priority to mitigate environmental pressures. Our study provides a novel perspective of sector-specific and province-typical policy recommendations for mitigating energy-water nexus pressures in China's supply chain networks. • Betweenness-based method combining with the MRIO model is used. • Regional transmission sectors of energy-water nexus pressures are identified. • Metallurgy is the key transmission sector in about a third of the provinces. • Fixed capital formation impacted greatly energy-water nexus pressures. [ABSTRACT FROM AUTHOR]

Considering the serious health burden caused by adverse weather events, increasing researches focused on the relationship between temperature variability (TV) and cause-specific mortality, but its association with cancer was not well explored. We aimed to investigate the impacts of TV on cancer mortality and examine the modifying effects of weather type and geographical location as well as other characteristics. Daily city-specific data of cancer deaths, mean temperature (Tmean), maximum and minimum temperatures (Tmax and Tmin), relative humidity (RH), rainfall, and air pollutants were collected during 2016–2017 in 13 cities in Jiangsu Province, China. TV 0-t was defined as the standard deviation of the daily Tmax and Tmin on the exposure 0-t days. A two-stage analysis was applied. First, a time-stratified case-crossover design was used to examine the odds ratio (OR) and attributable fraction of cancer mortality per 1 °C increase in TV by adjusting for potential confounders. Random effect meta-analysis was used to summarize the pooled ORs. Second, stratified analysis was performed for weather type, geographical location, demographics, and other city-level characteristics. The weather was defined as four types according to days during warm or cold season combined with high or low RH. A total of 303670 cases were included in our study. Meta-analysis showed that the ORs of cancer mortality per 1 °C increase in TV 0-t significantly increased and peaked in TV 0-2 (OR=1.0098, 95% CI: 1.0039–1.0157). The attributable fraction of TV 0-2 on cancer mortality was 4.74%, accounting for 14395 deaths in the study period. Significant ORs of TV-related cancer mortality were found during the warm season combined with high RH and in the northern region of Jiangsu. Susceptible groups of TV-related cancer mortality were identified as female patients, patients aged 45–65 years, and those living in cities with lower per capita green area. TV can significantly increase the risk of cancer mortality, especially during warm and humid days and in the northern region of Jiangsu. Findings are of great significance to formulate urban planning, resource allocation, and health intervention to prolong the life of cancer patients. • Temperature variability (TV) significantly increased the risk of cancer mortality. • TV-related cancer deaths were higher on warm and humid days and northern region. • Females patients and patients aged 45–65 years were more susceptible to TV. • A high level of per capita green area decreased the impacts of TV on cancer death. [ABSTRACT FROM AUTHOR]

Zinc is an essential trace element and a number of studies have identified the importance of zinc in neurodevelopment in children. However, epidemiologic data on the associations of zinc and genetic susceptibility with the risk of dyslexia are limited. We aimed to investigate whether genetic polymorphisms in GRIN2B genes modify the association between zinc levels and dyslexia risk. A case-control study of 240 dyslexic children and 230 healthy controls was conducted in Wuhan, Hangzhou and Jining city in China from April 2017 to April 2018. Zinc concentrations in urine samples were measured with inductively coupled plasma-mass spectrometry (ICPMS). Multiple imputation was used to impute missing values of covariates. We applied multivariable logistic regression models to evaluate the effect in the study. After adjustment for potential confounders, we observed the associations of urinary zinc with dyslexia risk were modified by rs1805502 (P interaction = 0.048) in gene GRIN2B. About 2-fold increase in creatinine-corrected zinc levels was significantly related to a reduced risk of dyslexia [odds ratio (OR) = 0.53, 95% confidence interval (CI): 0.29, 0.95 in rs1805502 mutation carriers]. The associations between zinc levels and dyslexia risk were modified by polymorphism of rs1805502 in gene GRIN2B. Image 1 [ABSTRACT FROM AUTHOR]

• A novel BTC measurement method based on event capture technique is proposed. • BTC values are solved based on the relationship between the counts of events and BTC distribution. • Accuracy, sensitivity, range and stability are demonstrated by the relationship equations. • A test to validate the proposed method in BTC measurement for a turboengine is performed. • Comparing with continuous sampling method, the measurement error is within 0.01 mm, and hardware occupation is reduced to 0.1%. Blade tip clearance (BTC) measurement is an essential technology in turbomachinery health monitoring so as to enhance efficiency and reliability as well as to ensure timely maintenance. The existing BTC measurement methods, which based on continuous sampling technique, depend highly on the devices sampling frequency, data transmission speed, storage memory, and computation capability, can hardly achieve online real-time measurement and long-term continuous monitoring. BTC distribution of a turbomachinery possesses discreteness, symmetry, monotonicity and quasi-periodicity, based on these characteristics, this paper proposes a novel BTC measurement method based on event capture technique. The method sorts the sensors signal into distinct events according to pre-set trigger thresholds, describes the relationship between the event kinds and the BTC distribution via mathematical equations, and solves the BTC values accordingly. The measurement error, measuring sensitivity, measurable range, and solving stability of the proposed method are demonstrated. A test to validate the proposed method for BTC measurement in the inlet section of a turboengine is performed, and the results show that, the event capture technique is capable of achieving fast and accurate BTC measurement. The proposed methods own a measurement error within 0.02 mm (for dual-channel configuration) and 0.01 mm (for multi-channel configuration) comparing with the continuous sampling technique. Meanwhile their hardware resource requirement are reduced to 0.02% (for dual-channel configuration) and 0.1% (for multi-channel configuration) comparing with the continuous sampling technique. For processing these performances, the proposed method can be applied for online real-time BTC measurement and long-term continuous BTC monitoring. [ABSTRACT FROM AUTHOR]

Melatonin has been demonstrated to protect against calcification in cyclosporine nephrotoxicity. Autophagy may affect vascular calcification by inhibiting apoptosis and the transdifferentiation process. This study sought to explore whether melatonin attenuates vascular calcification by regulating autophagy via the AMP-activated protein kinase/mammalian target of rapamycin/Unc-51-like kinase 1 (AMPK/mTOR/ULK1) signaling pathway. The effects of melatonin on vascular calcification were investigated in vascular smooth muscle cells (VSMCs). Calcium deposits were visualised by Alizarin red staining, while calcium content and alkaline phosphatase (ALP) activity were used to evaluate osteogenic differentiation. Western blots were used to measure expression of runt-related transcription factor 2 (Runx2, an osteogenic transcription factor), light chain 3 (LC3) II/I, and cleaved caspase 3. Melatonin markedly reduced calcium deposition and ALP activity. Runx2 and cleaved caspase 3 were downregulated, whereas LC3 II/I was increased in response to melatonin, and was accompanied by decreased apoptosis. An immunofluorescence assay revealed that melatonin treatment markedly decreased Runx2 expression and upregulated LC3 expression. Treatment with the autophagy inhibitor 3-methyladenine reversed this phenomenon. Melatonin significantly increased expression of p-AMPK and p-ULK1, and decreased mTOR expression. Treatment with compound C (an inhibitor of AMPK) or MHY1485 (an agonist of mTOR) ablated the observed benefits of melatonin treatment. Melatonin protects VSMCs against calcification by activating autophagy via the AMPK/mTOR/ULK1 pathway. [ABSTRACT FROM AUTHOR]